Cancer incidence among Swedish patients exposed to radioactive thorotrast: a forty-year follow-up survey

Thorotrast is an alpha-particle-emitting radiological contrast medium that caused chronic exposure to internal alpha-particle radiation when it was administered systemically. Cancer incidence in 432 Swedish patients exposed to Thorotrast was evaluated by computerized linkage of the cohort with the Swedish Cancer Register. Standardized incidence ratios (SIRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population. A total of 170 cancers occurring in 152 individuals were reported, whereas only 57 cases were expected. The SIR was significantly increased for cancer at all sites (3.0), with the largest excesses noted for primary liver and gallbladder cancer (SIR = 39.2). Other significantly elevated risks were observed for liver cancer not specified as primary, small intestine cancer, stomach cancer, leukemia, kidney cancer, CNS tumors, and pancreatic cancer. Among women, there was a significantly increased risk for lung cancer, based on a small number. Our results show that cumulative radiation exposure is directly related to carcinogenesis in the liver and gallbladder, which is consistent with earlier findings. In addition, there may be a relationship between radiation exposure and the development of other solid tumors.     

Mortality after cerebral angiography with or without radioactive Thorotrast: an international cohort of 3,143 two-year survivors.

There are few studies on the long-term sequelae of radionuclides ingested or injected into the human body. Patients exposed to radioactive Thorotrast in the 1930s through the early 1950s provide a singular opportunity, since the administration of this radiographic contrast agent resulted in continuous exposure to alpha particles throughout life at a low dose rate. We evaluated cause-specific mortality among an international cohort of 3,143 patients injected during cerebral angiography with either Thorotrast (n = 1,736) or a similar but nonradioactive agent (n = 1,407) and who survived 2 or more years. Standardized mortality ratios (SMRs) for Thorotrast and comparison patients were calculated, and relative risks (RR), adjusted for population, age and sex, were obtained by multivariate statistical modeling. Most patients were followed until death, with only 94 (5.4%) of the Thorotrast patients known to be alive at the closure of the study. All-cause mortality (n = 1,599 deaths) was significantly elevated among Thorotrast subjects [RR 1.7; 95% confidence interval (CI) 1.5-1.8]. Significantly increased relative risks were found for several categories, including cancer (RR 2.8), benign and unspecified tumors (RR 1.5), benign blood diseases (RR 7.1), and benign liver disorders (RR 6.5). Nonsignificant increases were seen for respiratory disease (RR 1.4) and other types of digestive disease (RR 1.6). The relative risk due to all causes increased steadily after angiography to reach a threefold RR at 40 or more years (P < 0.001). Excess cancer deaths were observed for each decade after Thorotrast injection, even after 50 years (SMR 8.6; P < 0.05). Increasing cumulative dose of radiation was directly associated with death due to all causes combined, cancer, respiratory disease, benign liver disease, and other types of digestive disease. Our study confirms the relationship between Thorotrast and increased mortality due to cancer, benign liver disease, and benign hematological disease, and suggests a possible relationship with respiratory disorders and other types of digestive disease. The cumulative excess risk of cancer death remained high up to 50 years after injection with >20 ml Thorotrast and approached 50%.     

Mortality after radiological investigation with radioactive Thorotrast: a follow-up study of up to fifty years in Portugal

Cerebral angiography using a radioactive radiological contrast medium, Thorotrast, was pioneered by Moniz in Portugal in the 1920s. Thorotrast is retained by the reticuloendothelial system, with a biological half-life of several hundred years, so that such patients suffer lifetime exposure to internal radiation. We studied mortality in Portuguese patients who were administered Thorotrast during the period 1928-1959 and in a comparison group of patients who received nonradioactive contrast agents. There were 1096 systemically exposed, 1014 unexposed, and, unique to the Portuguese study, 240 locally exposed Thorotrast patients who were successfully traced and followed up to the end of 1996. Mortality was significantly raised among systemically exposed Thorotrast patients relative to those unexposed for all causes [relative risk (RR) = 2.63], all neoplasms (RR = 6.72), liver cancer (RR = 42.4), chronic liver disease (RR = 5.12), other non-neoplastic diseases of the digestive system (RR = 4.87), neoplastic (RR = 21.9) and non-neoplastic hematological disorders (RR = 6.00), and non-neoplastic diseases of the respiratory system (RR = 4.31). Risks for most of these conditions increased significantly with time since first administration of the contrast medium and with cumulative alpha-particle radiation dose. Mortality was also significantly raised for non-neoplastic disorders of the nervous system (RR = 12.7) and ill-defined conditions (RR = 3.74), but these associations are likely to reflect the initial diagnosis, not Thorotrast exposure, because risks declined significantly with time and/or dose. There were no significant excess deaths from oropharyngeal or nasal cancers, or from any other cause, among patients exposed to Thorotrast locally for visualization of the perinasal sinuses, and no clear trend in risk with time since exposure. This study shows an association between systemic, but not local, exposure to Thorotrast and mortality from liver cancer, chronic liver disease, and neoplastic and non-neoplastic hematological disorders, with risks for these conditions remaining high for over 40 years after administration. Liver conditions, but not hematological disorders, showed a strong and consistent gradient with cumulative alpha-particle radiation dose.     

Mortality after long-term exposure to radioactive Thorotrast: a forty-year follow-up survey in Sweden

To evaluate temporal patterns of cause-specific mortality after long-term exposure to the alpha-particle-emitting contrast medium Thorotrast, we investigated a cohort consisting of 693 Swedish patients with neurological disorders who received Thorotrast during cerebral angiography, with follow-up ending in 1993. Standardized mortality ratios (SMRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population. Persons exposed to Thorotrast had significant excesses of all causes of death (SMR = 2.8; 95% CI 2.5-3.0), with similar increases noted for men and women. The largest risks were observed for deaths from hematological causes (SMR = 16.4; n = 8), cerebrovascular diseases (SMR = 10.1; n = 18), gastrointestinal disorders including liver cirrhosis (SMR = 5.2; n = 36), and tumors (SMR = 4.7; n = 187). There was a significant decrease in SMR with time since injection for cerebrovascular and circulatory diseases, indicative of the impact of underlying neurological disorders. In contrast, the SMR increased significantly with time for tumors and gastrointestinal diseases, suggestive of a detrimental effect of cumulative radiation dose. A significant dose-response relationship was found for all causes of death and malignant tumors among all age groups, and since SMR increased with time for the latter category, this is consistent with an effect of cumulative radiation exposure on cancer development. However, the findings should be treated with caution, since selection bias may have influenced some of the results.     

Cancer incidence and mortality in populations living near uranium milling and mining operations in grants, New Mexico, 1950-2004

In a previous cohort study of workers engaged in uranium milling and mining activities near Grants, Cibola County, New Mexico, we found lung cancer mortality to be significantly increased among underground miners. Uranium mining took place from early in the 1950s to 1990, and the Grants Uranium Mill operated from 1958-1990. The present study evaluates cancer mortality during 1950-2004 and cancer incidence during 1982-2004 among county residents. Standardized mortality (SMR) and incidence (SIR) ratios and 95% confidence intervals (CI) were computed, with observed numbers of cancer deaths and cases compared to expected values based on New Mexico cancer rates. The total numbers of cancer deaths and incident cancers were close to that expected (SMR 1.04, 95% CI 1.01-1.07; SIR 0.97, 95% CI 0.92-1.02). Lung cancer mortality and incidence were significantly increased among men (SMR 1.11, 95% CI 1.02-1.21; SIR 1.40, 95% CI 1.18-1.64) but not women (SMR 0.97, 95% CI 0.85-1.10; SIR 1.01, 95% CI 0.78-1.29). Similarly, among the population of the three census tracts near the Grants Uranium Mill, lung cancer mortality was significantly elevated among men (SMR 1.57; 95% CI 1.21-1.99) but not women (SMR 1.12; 95% CI 0.75-1.61). Except for an elevation in mortality for stomach cancer among women (SMR 1.30; 95% CI 1.03-1.63), which declined over the 55-year observation period, no significant increases in SMRs or SIRs for 22 other cancers were found. Although etiological inferences cannot be drawn from these ecological data, the excesses of lung cancer among men seem likely to be due to previously reported risks among underground miners from exposure to radon gas and its decay products. Smoking, socioeconomic factors or ethnicity may also have contributed to the lung cancer excesses observed in our study. The stomach cancer increase was highest before the uranium mill began operation and then decreased to normal levels. With the exception of male lung cancer, this study provides no clear or consistent evidence that the operation of uranium mills and mines adversely affected cancer incidence or mortality of county residents.     

Effects of radiation on incidence of primary liver cancer among atomic bomb survivors.

We describe the radiation risk for primary liver cancers between 1958 and 1987 in a cohort of atomic bomb survivors in Hiroshima and Nagasaki, Japan. The analysis is based on a comprehensive pathology review of known or suspected liver neoplasms that generated 518 incident, first primary cases, mostly hepatocellular carcinoma. Excess relative risk from atomic bomb radiation was linear: 0.81 per sievert weighted liver dose (95% CI [0.32, 1.43]; P < 0.001). Males and females had similar relative risk so that, given a threefold higher background incidence in males, the radiation-related excess incidence was substantially higher in males. Excess risk peaked for those with age at exposure in the early 20s; there was essentially no excess risk in those exposed before age 10 or after age 45. Whether this was due to a difference in sensitivity or possible confounding by other factors could not be addressed retrospectively in the full cohort. A paucity of cholangiocarcinoma and hemangiosarcoma cases suggested that they are not significantly associated with whole-body radiation exposure, as they are with the internal alpha-particle-emitting radiological contrast medium Thorotrast. Because most of the radiation-related excess cases occurred among males, it is important to ascertain what factors put men at greater risk of radiation-related liver cancer.     

Incidence of Cancer in ANCA-Associated Vasculitis: A Meta-Analysis of Observational Studies

ObjectiveThe purpose of this paper is to examine cancer incidence in patients with ANCA-associated vasculitis (AASV) derived from population-based cohort studies by means of meta-analysis.MethodsRelevant electronic databases were searched for studies characterizing the associated risk of overall malignancy in patients with AASV. Standardized incidence rates (SIRs) with 95% confidence intervals (CIs) were used to evaluate the strength of association. We tested for publication bias and heterogeneity and stratified for site-specific cancers.ResultsSix studies (n = 2,578) were eventually identified, of which six provided the SIR for overall malignancy, five reported the SIR for non-melanoma skin cancer (NMSC), four for leukemia, five for bladder cancer, three for lymphoma, three for liver cancer, four for lung cancer, three for kidney cancer, four for prostate cancer, four for colon cancer and four for breast cancer. Overall, the pooled SIR of cancer in AASV patients was 1.74 (95%CI = 1.37–2.21), with moderate heterogeneity among these studies (I² = 65.8%, P = 0.012). In sub-analyses for site-specific cancers, NMSC, leukemia and bladder cancer were more frequently observed in patients with AASV with SIR of 5.18 (95%CI = 3.47–7.73), 4.89 (95%CI = 2.93–8.16) and 3.84 (95%CI = 2.72–5.42) respectively. There was no significant increase in the risk of kidney cancer (SIR = 2.12, 95%CI = 0.66–6.85), prostate cancer (SIR = 1.45, 95%CI = 0.87–2.42), colon cancer (SIR = 1.26, 95%CI = 0.70–2.27), and breast cancer (SIR = 0.95, 95%CI = 0.50–1.79). Among these site-specific cancers, only NMSC showed moderate heterogeneity (I² = 55.8%, P = 0.06). No publication bias was found by using the Begg’s test and Egger''s test.ConclusionsThis meta-analysis shows that AASV patients treatment with cyclophosphamide (CYC) are at increased risk of late-occurring malignancies, particularly of the NMSC, leukemia and bladder cancer. However, there is no significant association between AASV and kidney cancer, prostate cancer, colon cancer and breast cancer. These findings emphasize monitoring and preventative management in AASV patients after cessation of CYC therapy is momentous.     

Radiation exposure and cancer incidence in a cohort of nuclear power industry workers in the Republic of Korea, 1992–2005

This study examines for the first time cancer incidence between radiation and non-radiation workers in nuclear power facilities in the Republic of Korea. Radiation workers were defined as persons who were issued with a dosimeter at nuclear power facilities, until 2005. All analyses were conducted on male workers only (in total 16,236 individuals) because of the sparseness of females. Statistical analyses were carried out using the standardized incidence ratio (SIR), to compare the cancer risks of radiation and non-radiation workers with those of the general population, and the χ² trend test was used to investigate any increase in cancer rates with dose. Poisson regression was also used to estimate the rate ratio (RR) and the excess relative risk (ERR) after considering the confounding effect due to smoking. During 1992–2005, 99 cancer cases in 63,503 person-years were observed among 8,429 radiation workers, while 104 cancer cases were observed in 48,301 person-years among 7,807 non-radiation workers. When compared with the site- and age-specific cancer rates for the male population of Korea, the SIR for all cancers combined was 1.07 [95% confidence interval (CI) 0.87–1.30] for radiation workers, and 0.88 (95% CI 0.72–1.06) for non-radiation workers, respectively. The RR for radiation workers compared with non-radiation workers was 1.18 (95% CI 0.89–1.58) for all cancers combined. The SIRs for thyroid cancer were noticeably high for both radiation and non-radiation workers, possibly due to the screening effect, but analysis of the RR showed that there was no statistically significant difference in thyroid cancer incidence rates between the two groups. For lung cancer, radiation workers showed a higher incidence rate as compared to non-radiation workers, with the RR being 3.48 (95% CI 1.19–11.48). A χ² trend test showed that there was no evidence for an increase in cancer rate with increasing cumulative dose for all cancers combined (p = 0.5108). The ERR per Sievert was estimated to be 1.69 (95% CI −2.07 to 8.21) for all cancers combined assuming a 10 years lag time. Consequently, a significant excess of cancer incidence among radiation workers in the nuclear power industry in Korea was not observed. Further follow-up and an expansion of the cohort are needed to overcome the lack of statistical power in the study.     

Cancer risk and all-cause mortality among Norwegian military United Nations peacekeepers deployed to Kosovo between 1999 and 2011

ObjectiveMedia reports of leukaemia and other cancers among European United Nations (UN) peacekeepers who served in the Balkans, and a scientific finding of excess Hodgkin lymphoma among Italian UN peacekeepers who served in Bosnia, suggested a link between cancer incidence and depleted uranium (DU) exposure. This spurred several studies on cancer risk among UN peacekeepers who served in the Balkans. Although these studies turned out to be negative, the debate about possible cancers and other health risks caused by DU exposure continues. The aim of the present study was to investigate cancer incidence and all-cause mortality in a cohort of 6076 (4.4% women) Norwegian military UN peacekeepers deployed to Kosovo between 1999 and 2011.MethodsThe cohort was followed for cancer incidence and mortality from 1999 to 2011. Standardised incidence ratios for cancer (SIR) and mortality ratios (SMR) were calculated from national rates.ResultsSixty-nine cancer cases and 38 deaths were observed during follow-up. Cancer incidence in the cohort was similar to that in the general Norwegian population. No cancers in the overall cohort significantly exceeded incidence rates in the general Norwegian population, but there was an elevated SIR for melanoma of skin in men of 1.90 (95% confidence interval [CI] 0.95–3.40). A fivefold increased incidence of bladder cancer was observed among men who served in Kosovo for ≥1 year, based on 2 excess cases (SIR = 5.27; 95% CI 1.09–15.4). All-cause mortality was half the expected rate (SMR = 0.49; 95% CI 0.35–0.67).ConclusionOur study did not support the suggestion that UN peacekeeping service in Kosovo is associated with increased cancer risk.     

Mortality (1950-1999) and cancer incidence (1969-1999) in the cohort of Eldorado uranium workers

This study assessed the relationship between radon decay product (RDP) exposure and mortality and cancer incidence in a cohort of 17,660 Eldorado uranium workers first employed in 1932-1980 and followed up through 1999. The analysis was based on substantially revised identifying information and dosimetry for workers from the Beaverlodge and Port Radium uranium mines and for the first time includes workers from a radium and uranium refinery and processing facility in Port Hope, Canada. Overall, male workers had lower mortality rates of all causes and all cancers and lower incidence rates of all cancers compared with the general Canadian male population, a likely healthy worker effect. Individual cancer rates were also reduced except for lung cancer mortality (SMR = 1.31, P < 0.001) and incidence (SIR = 1.23, P < 0.001). The excess relative risk per 100 WLM (ERR/100 WLM) of lung cancer mortality (N = 618, ERR/100 WLM = 0.55, 95% CI: 0.37, 0.78, P < 0.01) and incidence (N = 626, ERR/100 WLM = 0.55, 95% CI: 0.37, 0.81, P < 0.001) increased linearly with increasing RDP exposure. Adjustment for effect modification by time since exposure, exposure rate and age at risk resulted in comparable estimates of risk of lung cancer for all three uranium worksites. RDP exposures and γ-ray doses were not associated with any other cancer site or other cause of death. The risk estimates are in agreement with the results of the pooled analysis of 11 miner cohorts and more recent studies of uranium workers. The current analysis provides more precise risk estimates and compares the findings from the mortality study with the incidence study. Future follow-up of the cohort and joint analysis with other uranium miners' studies should shed more light on the effects of low RDP exposures as experienced by current workers as well as help to understand and address the health risks associated with residential radon.     

Malignant neoplasms after radiation therapy for peptic ulcer

Most information on radiation-related cancer risk comes from the Life Span Study (LSS) of the Japanese atomic bomb survivors. Stomach cancer mortality rates are much higher in Japan than in the U.S., making the applicability of LSS findings to the U.S. population uncertain. A unique cohort of U.S. patients who were irradiated for peptic ulcer to control gastric secretion provides a different perspective on risk. Cancer mortality data were analyzed and relative risks estimated for 3719 subjects treated by radiotherapy (mean stomach dose 14.8 Gy) and/or by surgery and medication during the period 1936-1965 and followed through 1997 (average 25 years). Compared to the U.S. rates, stomach cancer mortality was significantly increased for irradiated and nonirradiated patients (observed/expected = 3.20 and 1.52, respectively). We observed strong evidence of exposure-related excess mortality from cancer of the stomach (RR 2.6, 95% CI 1.3, 5.1), pancreas (RR 2.7, 95% CI 1.5, 5.1), and lung (RR 1.5, 95% CI 1.1, 2.1), with commensurate radiation dose responses in analyses that included nonexposed patients. However, the dose responses for these cancers were not significant when restricted to exposed patients. Our excess relative risk per gray estimate of 0.20 at doses 相似文献   

Cancer mortality following in utero exposure among offspring of female mayak worker cohort members

Little is known about long-term cancer risks following in utero radiation exposure. We evaluated the association between in utero radiation exposure and risk of solid cancer and leukemia mortality among 8,000 offspring, born from 1948-1988, of female workers at the Mayak Nuclear Facility in Ozyorsk, Russia. Mother's cumulative gamma radiation uterine dose during pregnancy served as a surrogate for fetal dose. We used Poisson regression methods to estimate relative risks (RRs) and 95% confidence intervals (CIs) of solid cancer and leukemia mortality associated with in utero radiation exposure and to quantify excess relative risks (ERRs) as a function of dose. Using currently available dosimetry information, 3,226 (40%) offspring were exposed in utero (mean dose = 54.5 mGy). Based on 75 deaths from solid cancers (28 exposed) and 12 (6 exposed) deaths from leukemia, in utero exposure status was not significantly associated with solid cancer: RR = 0.94, 95% CI 0.58 to 1.49; ERR/Gy = -0.1 (95% CI < -0.1 to 4.1), or leukemia mortality; RR = 1.65, 95% CI 0.52 to 5.27; ERR/Gy = -0.8 (95% CI < -0.8 to 46.9). These initial results provide no evidence that low-dose gamma in utero radiation exposure increases solid cancer or leukemia mortality risk, but the data are not inconsistent with such an increase. As the offspring cohort is relatively young, subsequent analyses based on larger case numbers are expected to provide more precise estimates of adult cancer mortality risk following in utero exposure to ionizing radiation.     

The Incidence Characteristics of Second Primary Malignancy after Diagnosis of Primary Colon and Rectal Cancer: A Population Based Study

Background

With the expanding population of colorectal cancer (CRC) survivors in the United States, one concerning issue is the risk of developing second primary malignancies (SPMs) for these CRC survivors. The present study attempts to identify the incidence characteristics of SPMs after diagnosis of first primary colon cancer (CC) and rectal cancer (RC).

Methods

189,890 CC and 83,802 RC cases were identified from Surveillance, Epidemiology and End Results Program (SEER) database. We performed rate analysis on incidence trend of SPMs in both CC and RC. Expected incidence rates were stratified by age, race and stage, calendar year of first CRC diagnosis and latency period since first CRC diagnosis. The standardized incidence ratios (SIRs), measure for estimating risk of SPMs, were calculated for CC and RC respectively.

Results

The trends of incidence of SPMs in both CC and RC were decreasing from 1992 to 2012. Both CC and RC survivors had higher risk of developing SPMs (SIRCC = 1.13; SIRRC = 1.05). For CC patients, the highest risks of SPM were cancers of small intestine (SIR = 4.03), colon (SIR = 1.87) and rectum (SIR = 1.80). For RC patients, the highest risks of SPMs were cancers of rectum (SIR = 2.88), small intestine (SIR = 2.16) and thyroid (SIR = 1.46). According to stratified analyses, we also identified incidence characteristics which were contributed to higher risk of developing SPMs, including the age between 20 and 40, American Indian/Alaska Native, localized stage, diagnosed at calendar year from 2002 to 2012 and the latency between 12 and 59 months.

Conclusions

Both CC and RC survivors remain at higher risk of developing SPMs. The identification of incidence characteristics of SPMs is extremely essential for continuous cancer surveillance among CRC survivors.     

Risk of Gastrointestinal Cancers among Patients with Appendectomy: A Large-Scale Swedish Register-Based Cohort Study during 1970-2009

Background

Removal of the appendix might induce physiological changes in the gastrointestinal tract, and subsequently play a role in carcinogenesis. Therefore, we conducted a nationwide register-based cohort study in Sweden to investigate whether appendectomy is associated with altered risks of gastrointestinal cancers.

Methods

A population-based cohort study was conducted using the Swedish national registries, including 480,382 eligible patients followed during the period of 1970–2009 for the occurrence of site-specific gastrointestinal cancer (esophageal/gastric/colon/rectal cancer). Outcome and censoring information was collected by linkage to health and demography registers. We examined the incidence of appendectomy in Sweden using data from 1987–2009. We also calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) to estimate the relative gastrointestinal cancer risk through comparison to the general population.

Results

We noted an overall decrease in the age-standardized incidence of appendectomy among the entire Swedish population from 189.3 to 105.6 per 100,000 individuals between 1987 and 2009. Grouped by different discharge diagnosis, acute appendicitis, incidental appendectomy, and entirely negative appendectomy continuously decreased over the study period, while the perforation ratio (18%–23%) stayed relatively constant. Compared to the general population, no excess cancer risk was observed for gastrointestinal cancers under study with the exception of a marginally elevated risk for esophageal adenocarcinoma (SIR 1.32, 95% CI 1.09–1.58).

Conclusions

In Sweden, the incidence of appendectomy and acute appendicitis has decreased during 1987–2009. No excess gastrointestinal cancer risks were observed among these appendectomized patients, with the possible exception of esophageal adenocarcinoma.     

Mortality patterns among industrial workers exposed to chloroprene and other substances. II. Mortality in relation to exposure

As part of an historical cohort study to investigate the mortality experience of industrial workers exposed to chloroprene (CD) and other substances, including vinyl chloride monomer (VC), we analyzed mortality from all cancers combined, respiratory system (RSC) and liver cancer in relation to CD and VC exposures. Subjects were 12,430 workers ever employed at one of two U.S. sites (Louisville, KY (n=5507) and Pontchartrain, LA (n=1357)) or two European sites (Maydown, Northern Ireland (n=4849) and Grenoble, France (n=717)). Historical exposures for individual workers were estimated quantitatively for CD and VC. For sites L, M, P and G, respectively, average intensity of CD exposures (median value of exposed workers in ppm) were 5.23, 0.16, 0.028 and 0.149 and median cumulative exposures (ppm years) were 18.35, 0.084, 0.133 and 1.01. For sites L and M, respectively, average intensity of VC exposures (median value of exposed workers in ppm) was 1.54 and 0.03 and median cumulative exposures (ppm years) were 1.54 and 0.094. We performed relative risk (RR) regression modeling to investigate the dependence of the internal cohort rates for all cancers combined, RSC and liver cancer on combinations of the categorical CD or VC exposure measures with adjustment for potential confounding factors. We categorized exposure measures into approximate quartiles based on the distribution of deaths from all cancers combined. We also considered 5- and 15-year lagged exposure measures and adjusted some RR models for worker pay type (white/blue collar) as a rough surrogate for lifetime smoking history. All modeling was site-specific to account for exposure heterogeneity. We also computed exposure category-specific standardized mortality ratios (SMRs) to assess absolute mortality rates. With the exception of a one statistically significant association with duration of exposure to CD and all cancers combined in plant M, we observed no evidence of a positive association with all cancers, RSC or liver cancer and exposure to CD and/or VC using both the unlagged and lagged exposure measures: duration, average intensity or cumulative exposure to CD or VC; time since first CD or VC exposure; and duration of CD exposure or time since first CD exposure in presence or absence of VC exposure. We observed elevated and statistically significantly elevated RRs for some analysis subgroups, but these were due to inordinately low death rates in the baseline categories. With the possible exception of all cancer mortality in plant G, our additional adjustment of RRs for pay type revealed no evidence of positive confounding by smoking. We conclude that exposures to CD or VC at the levels encountered in the four study sites do not elevate mortality risks from all cancers, RSC or liver cancer. This conclusion is corroborated by our analysis of general mortality patterns among the CD cohort reported in our companion paper [G. Marsh, A. Youk, J. Buchanich, M. Cunningham, N. Esmen, T. Hall, M. Phillips, Mortality patterns among industrial workers exposed to chloroprene and other substances. I. General mortality patterns, Chem.-Biol. Interact., submitted for publication].     

Mortality in people with schizophrenia: a systematic review and meta‐analysis of relative risk and aggravating or attenuating factors

People with schizophrenia die 15‐20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and random‐effects meta‐analysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was all‐cause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specific‐cause mortality. Publication bias, subgroup and meta‐regression analyses, and quality assessment (Newcastle‐Ottawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all‐cause mortality was increased in people with schizophrenia versus any non‐schizophrenia control group (RR=2.52, 95% CI: 2.38‐2.68, n=79), with the largest risk in first‐episode (RR=7.43, 95% CI: 4.02‐13.75, n=2) and incident (i.e., earlier‐phase) schizophrenia (RR=3.52, 95% CI: 3.09‐4.00, n=7) versus the general population. Specific‐cause mortality was highest for suicide or injury‐poisoning or undetermined non‐natural cause (RR=9.76‐8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79‐7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardio‐cerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). All‐cause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001‐0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased all‐cause and suicide‐related mortality compared to those ≥40 years old, and a higher percentage of females increased suicide‐related mortality risk in incident schizophrenia samples. All‐cause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased all‐cause mortality (RR=1.62, 95% CI: 1.47‐1.80, n=3). Antipsychotics were protective against all‐cause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59‐0.84, n=11), with largest effects for second‐generation long‐acting injectable anti­psychotics (SGA‐LAIs) (RR=0.39, 95% CI: 0.27‐0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34‐0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39‐0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44‐0.63, n=4). Antipsychotics were also protective against natural cause‐related mortality, yet first‐generation antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust the analyses moderated larger natural‐cause mortality risk, and more recent study year moderated larger protective effects of antipsychotics. These results indicate that the excess mortality in schizophrenia is associated with several modifiable factors. Targeting comorbid substance abuse, long‐term maintenance antipsychotic treatment and appropriate/earlier use of SGA‐LAIs and clozapine could reduce this mortality gap.     

Lithuanian cohort of Chernobyl cleanup workers: Cancer incidence follow-up 1986–2012

BackgroundCancer risks following radiation exposure in adulthood after Chernobyl are less studied compared to those after exposure in childhood. We aimed to evaluate cancer risk in the Lithuanian cohort of Chernobyl cleanup workers 26 years after their exposure in Chernobyl.MethodsStudy population (6707 men) was followed for cancer incidence upon return from Chernobyl till the end of 2012 by linkage procedure with the Lithuanian Cancer Registry and for migration and death – with Central Population Registry. The site-specific cancer risk in the cohort was estimated by calculating the standardised incidence ratio (SIR) with 95 % confidence interval (CI).ResultsA total of 596 cancer cases was observed in the cohort, against 584 expected (SIR 1.02; 95 % CI 0.94, 1.11). Only incidence of mouth and pharynx cancers was increased compared to the expected (SIR 1.41; 95 % CI 1.07, 1.86). Nevertheless, an increased risk of thyroid cancer was observed among cleanup workers who were younger than 30 years when entering the Chernobyl zone (SIR 2.90; 95 % CI 1.09, 7.72), whose radiation dose was above 100 milisievert (mSv) (SIR 3.13; 95 % CI 1.30, 7.52) and who had shorter duration of stay (SIR 2.30; 95 % CI 1.03, 5.13).ConclusionsOur findings are consistent with those observed in other cohorts of workers, namely, the increased risk of cancer sites related to behavioural factors. The increased risk of thyroid cancer among cleanup workers who were younger than 30 years when entering Chernobyl and whose radiation dose was above 100 mSv cannot exclude the association with the radiation exposure in Chernobyl.     

Risk of primary haematologic cancers following incident non-metastatic breast cancer: A Danish population-based cohort study

BackgroundBreast cancer survivors may have increased risk of subsequent haematologic cancer. We compared their risk of haematologic cancers with the general population during 38 years of follow-up.MethodsUsing population-based Danish medical registries, we assembled a nationwide cohort of women diagnosed with incident non-metastatic breast cancer during 1980–2017, with follow-up through 2018. We compared breast cancer survivors with the general population by computing standardised incidence ratios (SIR) and 95% confidence intervals (CI).ResultsAmong 101,117 breast cancer survivors, we observed 815 incident haematologic cancers (median follow-up: 7.9 years). We observed excess risk of acute myeloid leukaemia (AML) (SIR: 1.65, 95%CI: 1.33–2.01), particularly in women who received chemotherapy (SIR: 3.33, 95%CI: 2.24–4.75) and premenopausal women (SIR: 3.23, 95%CI: 2.41–4.25). The risk of acute lymphoid leukaemia (ALL) was increased (SIR: 2.25, 95%CI: 1.29–3.66), whereas the risk of chronic lymphoid leukaemia (CLL) was decreased (SIR: 0.66, 95%CI: 0.53–0.82). An additional analysis showed elevated risk of CLL 0–6 months after breast cancer diagnosis (SIR: 3.00 95%CI: 1.75–4.80).ConclusionCompared to the general population, breast cancer survivors had elevated risk of AML, particularly when treated with chemotherapy. The risk of ALL was elevated, whereas the risk of CLL was lower. The higher risk of CLL in the first six months after diagnosis likely reflects surveillance bias—due to intensified diagnostic efforts at breast cancer diagnosis and treatment—prompting earlier detection. This has likely reduced the long-term risk of CLL in breast cancer survivors.     

Assessment of surveillance versus etiologic factors in the reciprocal association between papillary thyroid cancer and breast cancer

BackgroundMutually increased risks for thyroid and breast cancer have been reported, but the contribution of etiologic factors versus increased medical surveillance to these associations is unknown.MethodsLeveraging large-scale US population-based cancer registry data, we used standardized incidence ratios (SIRs) to investigate the reciprocal risks of thyroid and breast cancers among adult females diagnosed with a first primary invasive, non-metastatic breast cancer (N = 652,627) or papillary thyroid cancer (PTC) (N = 92,318) during 2000–2017 who survived ≥1-year.ResultsPTC risk was increased 1.3-fold [N = 1434; SIR = 1.32; 95 % confidence interval (CI) = 1.25–1.39] after breast cancer compared to the general population. PTC risk declined significantly with time since breast cancer (Poisson regression = P_trend <0.001) and was evident only for tumors ≤2 cm in size. The SIRs for PTC were higher after hormone-receptor (HR)+ (versus HR-) and stage II or III (versus stage 0-I) breast tumors. Breast cancer risk was increased 1.2-fold (N = 2038; SIR = 1.21; CI = 1.16–1.26) after PTC and was constant over time since PTC but was only increased for stage 0-II and HR + breast cancers.ConclusionAlthough some of the patterns by latency, stage and size are consistent with heightened surveillance contributing to the breast-thyroid association, we cannot exclude a role of shared etiology or treatment effects.     

Cancer mortality following radium treatment for uterine bleeding

Cancer mortality in relation to radiation dose was evaluated among 4153 women treated with intrauterine radium (226Ra) capsules for benign gynecologic bleeding disorders between 1925 and 1965. Average follow up was 26.5 years (maximum = 59.9 years). Overall, 2763 deaths were observed versus 2687 expected based on U.S. mortality rates [standardized mortality ratio (SMR) = 1.03]. Deaths due to cancer, however, were increased (SMR = 1.30), especially cancers of organs close to the radiation source. For organs receiving greater than 5 Gy, excess mortality of 100 to 110% was noted for cancers of the uterus and bladder 10 or more years following irradiation, while a deficit was seen for cancer of the cervix, one of the few malignancies not previously shown to be caused by ionizing radiation. Part of the excess of uterine cancer, however, may have been due to the underlying gynecologic disorders being treated. Among cancers of organs receiving average or local doses of 1 to 4 Gy, excesses of 30 to 100% were found for leukemia and cancers of the colon and genital organs other than uterus; no excess was seen for rectal or bone cancer. Among organs typically receiving 0.1 to 0.3 Gy, a deficit was recorded for cancers of the liver, gall bladder, and bile ducts combined, death due to stomach cancer occurred at close to the expected rate, a 30% excess was noted for kidney cancer (based on eight deaths), and there was a 60% excess of pancreatic cancer among 10-year survivors, but little evidence of dose-response. Estimates of the excess relative risk per Gray were 0.006 for uterus, 0.4 for other genital organs, 0.5 for colon, 0.2 for bladder, and 1.9 for leukemia. Contrary to findings for other populations treated by pelvic irradiation, a deficit of breast cancer was not observed (SMR = 1.0). Dose to the ovaries (median, 2.3 Gy) may have been insufficient to protect against breast cancer. For organs receiving greater than 1 Gy, cancer mortality remained elevated for more than 30 years, supporting the notion that radiation damage persists for many years after exposure.